Contribution of Active and Inactive States of the Human 5-HT4d Receptor to the Functional Activities of 5-HT4-Receptor Agonists

• Mikami Tadayoshi

  Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Japan

• Sugimoto Hiromi

  Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Japan

• Naganeo Rie

  Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Japan

• Ohmi Takashi

  Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Japan

• Saito Toshiyuki

  Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Japan

• Eda Hiroyuki

  Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Japan

Abstract

In the present study, binding affinities of 5-hydroxytryptamine-4 (5-HT₄) ligands for the human 5-HT_4d receptor were determined using the agonist [³H]5-HT and the selective 5-HT₄ antagonist [³H]GR113,808. We also compared the affinity differences between [³H]5-HT binding (K_H) and [³H]GR113,808 binding (K_L) with their activities as 5-HT₄ ligands. Binding studies using [³H]5-HT revealed that the human 5-HT_4d receptor has two binding sites, whereas [³H]GR113,808 yielded a single binding site. Additionally, the number of [³H]5-HT binding sites decreased in the presence of guanosine-5'-O-(3-thiotriphosphate) (GTPγS), but the number of [³H]GR113,808 sites did not change. In competitive binding assays, full agonists such as 5-methoxytryptamine and tegaserod showed 2- to 8-fold higher affinities for [³H]5-HT binding (K_H) than for [³H]GR113,808 binding (K_L) (K_H<K_L). Conversely, antagonists showed lower affinities for [³H]5-HT binding than for [³H]GR113,808 binding (K_H>K_L). Finally, partial agonists displayed similar binding affinities for both radioligands (K_H = K_L). These findings suggest that the equilibrium between active and inactive states of the human 5-HT_4d receptor relies on the functional activities of 5-HT₄ ligands, and these states affect the affinities of 5-HT₄ ligands in the competitive binding assay.<br>

Journal

• Journal of Pharmacological Sciences

  Journal of Pharmacological Sciences 107 (3), 251-259, 2008

  The Japanese Pharmacological Society

Keywords

• 5-hydroxytryptamine-4 (5-HT₄) receptor
• agonist
• antagonist
• serotonin
• GR113808

Details

• CRID: 1390001205179725440
• NII Article ID: 10024321238
• NII Book ID: AA11806667
• DOI: 10.1254/jphs.fp0072230
• ISSN: 13478648
• ISSN: 13478613
• NDL BIB ID: 9583041
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I9583041
• Web Site: https://search.jamas.or.jp/link/ui/2009001683
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
• Abstract License Flag: Disallowed